DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212

By J. Kim, Xin Duan, Cindy Y. Liu, M. Jang, Junjie U. Guo, Nattapol Pow-anpongkul, Eunchai Kang, Hongjun Song, Guo-li Ming. 2009

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SUMMARY Disrupted-in-Schizophrenia 1 (DISC1), a susceptibility gene for major mental illnesses, regulates multiple aspects of embryonic and adult neurogenesis. Here we show that DISC1 suppression in newborn neurons of the adult hippocampus leads to over-activated signaling of AKT, another schizophrenia susceptibility gene. Mechanistically, DISC1 directly interacts with KIAA1212, an AKT binding partner that enhances AKT signaling in the absence of DISC1, and DISC1 binding to KIAA1212 prevents AKT activation in vitro. Functionally, multiple genetic manipulations to enhance AKT signaling in adult-born neurons in vivo exhibit similar defects as DISC1 suppression in neuronal development that can be rescued by pharmacological inhibition of mammalian target of rapamycin (mTOR), an AKT downstream effector. Our study identifies AKT-mTOR signaling pathway as a critical DISC1 target in regulating neuronal development and provides a framework for understanding how multiple susceptibility genes may functionally converge onto a common pathway in contributing to the etiology of certain psychiatric disorders.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

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Citations in the corpus

Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions (2011, background): “…disorders) promotes proliferation of neural progenitors through the GSK3b/b-catenin pathway (Mao et al., 2009) while limiting dendritic growth and synapse formation of new neurons through AKT/mTOR signaling in the adult hippocampus (Duan et al., 2007; Faulkner et al., 2008; Kim et al., 2009).”
In vivo clonal analysis reveals self-renewing and multipotent adult neural stem cell characteristics (2011, neutral): “Immunostaining of PTEN confirmed its deletion in GFP+ cells in PTEN cKO mice (Figure S6B).”